Systemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health (NIH), Bethesda, MD, United States.
Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, United States.
Front Immunol. 2018 Jul 26;9:1680. doi: 10.3389/fimmu.2018.01680. eCollection 2018.
Increasing evidence suggests that neutrophil extracellular traps (NETs) may play a role in promoting atherosclerotic plaque lesions in humans and in murine models. The exact pathways involved in NET-driven atherogenesis remain to be systematically characterized. To assess the extent to which myeloid-specific peptidylarginine deiminase 4 (PAD4) and PAD4-dependent NET formation contribute to atherosclerosis, mice with myeloid-specific deletion of PAD4 were generated and backcrossed to Apoe mice. The kinetics of atherosclerosis development were determined. NETs, but not macrophage extracellular traps, were present in atherosclerotic lesions as early as 3 weeks after initiating high-fat chow. The presence of NETs was associated with the development of atherosclerosis and with inflammatory responses in the aorta. Specific deletion of PAD4 in the myeloid lineage significantly reduced atherosclerosis burden in association with diminished NET formation and reduced inflammatory responses in the aorta. NETs stimulated macrophages to synthesize inflammatory mediators, including IL-1β, CCL2, CXCL1, and CXCL2. Our data support the notion that NETs promote atherosclerosis and that the use of specific PAD4 inhibitors may have therapeutic benefits in this potentially devastating condition.
越来越多的证据表明，中性粒细胞胞外诱捕网（NETs）可能在促进人类和小鼠模型的动脉粥样硬化斑块病变中发挥作用。NET 驱动动脉粥样硬化形成的确切途径仍有待系统描述。为了评估髓样细胞特异性肽基精氨酸脱亚氨酶 4（PAD4）和 PAD4 依赖性 NET 形成在动脉粥样硬化中的作用程度，生成了髓样细胞特异性 PAD4 缺失的小鼠，并将其与 Apoe 小鼠进行回交。确定了动脉粥样硬化发展的动力学。早在启动高脂肪饲料后 3 周，NETs 就已经存在于动脉粥样硬化病变中，而不是巨噬细胞胞外诱捕网。NETs 的存在与动脉粥样硬化的发展以及主动脉中的炎症反应有关。髓系谱系中 PAD4 的特异性缺失与 NET 形成减少和主动脉炎症反应降低相关，从而显著降低动脉粥样硬化负担。NETs 刺激巨噬细胞合成炎症介质，包括 IL-1β、CCL2、CXCL1 和 CXCL2。我们的数据支持这样的观点，即 NETs 促进动脉粥样硬化，并且使用特定的 PAD4 抑制剂在这种潜在的破坏性疾病中可能具有治疗益处。
